WO2001061027A1 - Procede de production de 1,2-epoxy-2,6,6-trimethylcyclohexane methanol optiquement actif - Google Patents

Procede de production de 1,2-epoxy-2,6,6-trimethylcyclohexane methanol optiquement actif Download PDF

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Publication number
WO2001061027A1
WO2001061027A1 PCT/JP2001/000882 JP0100882W WO0161027A1 WO 2001061027 A1 WO2001061027 A1 WO 2001061027A1 JP 0100882 W JP0100882 W JP 0100882W WO 0161027 A1 WO0161027 A1 WO 0161027A1
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Prior art keywords
epoxy
acetate
enzyme
trimethylcyclohexane
genus
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PCT/JP2001/000882
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English (en)
Japanese (ja)
Inventor
Hiromasa Kiyota
Ryou Okazaki
Takayuki Oritani
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Kuraray Co Ltd
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Kuraray Co Ltd
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Priority claimed from JP2000036545A external-priority patent/JP2001224396A/ja
Priority claimed from JP2000036546A external-priority patent/JP2001226363A/ja
Application filed by Kuraray Co Ltd filed Critical Kuraray Co Ltd
Publication of WO2001061027A1 publication Critical patent/WO2001061027A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/004—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of alcohol- or thiol groups in the enantiomers or the inverse reaction
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms

Definitions

  • the present invention relates to a method for producing optically active 1,2-epoxy-2,6,6-phenol.
  • the (+)-(1R, 2R) —1,2-epoxy-1,2,6,6-trimethylcyclohexanemethanol obtained by the present invention has, for example, an activity equivalent to that of an optically active abscisic acid, which is a plant hormone. It is useful as an intermediate for the synthesis of epoxy 1 / 3-ionylidene acetic acid having Background art
  • the method for producing optically active 1,2-epoxy-2,6,6-trimethylcyclohexanemethanol is based on the asymmetric epoxidation reaction of 2,6,6-trimethyl-1-cyclohexenemethanol developed by Shearpres et al.
  • a method of obtaining 95% e.e. of the target compound by the method [see Phytochemistry, Vol. 22, p. 1909 (1983)] is known.
  • the above method is an (+)-(1R, 2R)-1,2-epoxy-2,6,6-trimethylcyclo which is an intermediate for the synthesis of epoxy 1 / 3-ionylideneacetic acid with high plant hormone-like activity.
  • an unnatural tartrate ester which is an expensive asymmetric ligand, must be used. Is hard to say.
  • an object of the present invention is to produce an optically active 1,2-epoxy-2,6,6-trimethylcyclohexanemethanol with a high yield and high optical purity in an industrially advantageous manner. It is to provide a method. Disclosure of the invention
  • Equation (3) Acetate is reacted with 1,2-epoxy-1,2,6,6-anol (hereinafter abbreviated as alcohol (3)) represented by the following formula in the presence of an enzyme capable of asymmetric acylation.
  • alcohol (3) 1,2-epoxy-1,2,6,6-anol
  • Enzymes having ester hydrolytic ability to act on acetate (1) include enzymes produced by microorganisms belonging to the genus Pseudomonas and enzymes produced by microorganisms belonging to the genus Burkh olderiacepacia.
  • Lipase P (manufactured by Nagase & Co., Ltd.), Lipase P (manufactured by Amano Pharmaceutical Co., Ltd.), Lipase PS '(manufactured by Amano Pharmaceutical Co., Ltd.), Lipase PS 30 (manufactured by Amano Pharmaceutical Co., Ltd.) (Manufactured by Roche's Diagnostics Co., Ltd.), which is an enzyme produced by a microorganism belonging to the genus Burkho lderiacepacia.
  • the (+)-(1R, 2R) -alcohol (2) can be prepared with high optical purity because the (-)-(1R, 2R) form of the acetate '(1) is preferentially hydrolyzed. It can be obtained in yield.
  • the amount of the enzyme that has the ability to hydrolyze esters is usually 0.01 to 200 times the amount of acetate (1). % Is preferred, and a range of 0.1 to 100% by weight is more preferred.
  • the reaction is preferably performed in the presence of a solvent.
  • a solvent examples include ethers such as getyl ether, diisopropyl ether and t-butyl methyl ether; nitriles such as acetonitrile; ketones such as acetone; and hydrocarbons such as toluene and hexane.
  • diisopropyl ether is particularly preferred.
  • the amount of the solvent used is usually preferably in the range of 5 to 100 times by weight, more preferably in the range of 10 to 40 times by weight, relative to the acetate (1).
  • the pH of the reaction solution is preferably kept at 4 to 8.
  • the pH is adjusted by adding phosphate buffer or acetate buffer to the reaction system. It is particularly preferable to carry out the reaction in the presence of a buffer such as a liquid.
  • the amount of the buffer used is not particularly limited, but is usually preferably from 1 to 100 times by weight, more preferably from 10 to 40 times by weight, based on the acetate (1).
  • the reaction temperature is preferably in the range of 0 to 40 ° C, more preferably in the range of 10 to 30 ° C.
  • the reaction time varies depending on the ratio of the acetate (1) to the enzyme capable of hydrolyzing the ester, the solvent used, the type of buffer, and the like, but the reaction usually ranges from 1 hour to 1 week. ), An enzyme having the ability to hydrolyze an ester, a solvent and, if necessary, a buffer solution, and then stirring at a predetermined temperature.
  • the reaction may be carried out in a batch mode, or may be carried out in a continuous mode using an immobilized enzyme having an ester hydrolytic ability.
  • Isolation of the (+)-(1R, 2R) -alcohol (2) thus obtained from the reaction mixture is carried out in the same manner as that used for ordinary isolation and purification of organic compounds. be able to.
  • an enzyme having ester hydrolysis ability is filtered from the reaction mixture, the filtrate is extracted with getyl ether, diisopropyl ether, ethyl acetate, etc., and the extract is washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate and concentrating, the product obtained is concentrated by column chromatography, etc. To purify.
  • acetate for example, piper acetate, probenyl acetate, trichloroethyl acetate and the like can be mentioned.
  • the use amount of the acetic ester is preferably in the range of 0.5 to 10 equivalents to the alcohol (3).
  • Enzymes having asymmetric acylation ability include enzymes produced by microorganisms belonging to the genus Pseudomonas, enzymes produced by microorganisms belonging to the genus Burkh olderiacepacia, and enzymes produced by microorganisms belonging to the genus Mu cormiehei. There are enzymes derived from pig knees.
  • Rivase P manufactured by Nagase & Co., Ltd.
  • lipase P manufactured by Amano Pharmaceutical Co., Ltd.
  • Riva which are enzymes produced by microorganisms belonging to the genus Pseudomonas Ichize PS (manufactured by Amano Pharmaceutical Co., Ltd.)
  • Kirazaim L-1 an enzyme produced by a microorganism belonging to the genus Burkho lderiacepacia, c.-f.
  • Mu cormiehei Examples include Kirazam L-19, cf., C2, which is an enzyme produced by a microorganism belonging to the genus, and pancretin, which is an enzyme derived from pig kidney.
  • lipase P manufactured by Nagasaki Industry Co., Ltd.
  • the amount of the enzyme having asymmetric acylation ability to be used is generally preferably in the range of 0.01 to 200% by weight, more preferably in the range of 0.1 to 100% by weight, based on the alcohol (3).
  • the reaction is preferably performed in the presence of a solvent.
  • a solvent for example, Ethers such as toluene, diisopropyl ether and t-butyl methyl ether; nitriles such as acetonitrile; ketones such as acetone; and hydrocarbons such as toluene and hexane.
  • Ethers such as toluene, diisopropyl ether and t-butyl methyl ether
  • nitriles such as acetonitrile
  • ketones such as acetone
  • hydrocarbons such as toluene and hexane.
  • the amount of the solvent used is usually preferably in the range of 5 to 100 times by weight, more preferably in the range of 10 to 50 times by weight, relative to the alcohol (3).
  • the reaction temperature is preferably in the range of 0 to 40 ° C, more preferably in the range of 10 to 30 ° C.
  • the reaction time varies depending on the ratio of the alcohol (3) to the enzyme having asymmetric acylation ability and the type of the solvent used, but is usually in the range of 1 hour to 1 week.
  • the reaction is preferably carried out by mixing alcohol, (3), acetate, an enzyme capable of asymmetric acylation and a solvent, and stirring the mixture at a predetermined temperature.
  • the reaction may be performed in a patch system, or may be performed in a continuous system using an immobilized enzyme capable of asymmetric acylation.
  • Isolation of the (-)-(1R, 2R) -acetate (4) thus obtained from the reaction mixture can be performed in the same manner as that used for ordinary isolation and purification of organic compounds.
  • an enzyme having an asymmetric acylation ability is filtered from the reaction mixture, and the filtrate is concentrated, and the obtained product is purified by column chromatography or the like. .
  • the solvolysis reaction can be performed in the presence of a basic substance or an acidic substance for the purpose of accelerating the reaction.
  • a basic substance or an acidic substance for the purpose of accelerating the reaction.
  • basic substances include amines such as triethylamine, hydrazine and pyridine; alkali metal alkoxides such as sodium methoxide and potassium t-butoxide; alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; sodium carbonate Metal carbonates such as carbon dioxide lime.
  • the acidic substance include protic acids such as hydrochloric acid and sulfuric acid; and Lewis acids such as titanium tetrachloride and boron trifluoride.
  • the amount of the basic substance or acidic substance used it is usually 0 per 1 (1R, 2R) acetate (4). The range is preferably from 2 to 2 moles, more preferably from 0.5 to 1 mole.
  • the reaction is performed in the presence of water; an alcohol such as methanol, ethanol, propanol, or butanol; or a mixture of water and an alcohol.
  • an alcohol such as methanol, ethanol, propanol, or butanol
  • a mixture of water and an alcohol There is no particular limitation on the amount of water, alcohol or a mixture of water and alcohol, but it is usually 5 to 300 times the weight of (1) 1 (1 R, 2 R) -acetato (4). Is preferable.
  • a solvent that does not adversely affect the reaction may be further co-existed, and the solvent may be, for example, heptane, an aliphatic or aromatic hydrocarbon such as san, heptane, cyclohexane, benzene, toluene, or xylene. And ethers such as getyl ether, diisopropyl ether, tetrahydrofuran, 1,4-dioxane and the like. These solvents may be used alone or as a mixture of two or more. When the above-mentioned solvent is allowed to coexist, there is no particular limitation on the amount of the solvent, but it is usually preferably in the range of 1 to 200 times the weight of (1)-(1R, 2R) -acetate (4).
  • the reaction temperature is preferably in the range of 0 to 100 ° C, more preferably in the range of 20 to 50.
  • the reaction time varies depending on the reaction conditions, but is usually within 8 hours.
  • the (+)-(1R, 2R) -alcohol (2) obtained in this way can be isolated and purified by the methods commonly used for the isolation and purification of organic compounds.
  • the reaction solution is extracted by adding an organic solvent such as ethyl acetate, geethyl ether, methylene chloride, etc., and the extract is washed with dilute hydrochloric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a saturated aqueous solution of sodium chloride, etc., and dried over anhydrous magnesium sulfate.
  • the crude product obtained by concentration is purified by column chromatography, recrystallization, distillation, etc.
  • the alcohol (3) which is a starting material of the present invention, is obtained by treating / 3-ionone with ozone and then with sodium borohydride, 2,6,6-trimethyl-1-cyclohexenemethanol [Journal Organic Chemistry (J. Org. Chem.), Vol. 61, pp. 519-196 (1996)], the double bond of methacrylic acid, chloroperbenzoic acid, etc. Can be easily manufactured by epoxidation using an oxidizing agent
  • Acetate (1) is the alcohol obtained by the above method. It can be easily produced by converting the hydroxyl group of (3) into acetyl with acetic anhydride or the like (see Reference Examples 1 and 2).
  • 2,6,6-Trimethyl-1-cyclohexenemethanol (7.2 g, 47 mmo 1) and sodium bicarbonate (1.0 g, 29 mmo 1) are suspended in dry black-mouthed form to zero.
  • metabenzo-perbenzoic acid (9.5 g, 55 mmo 1) was added while maintaining the internal temperature at 0 ° C. or less, and after the addition was completed, the mixture was stirred for 2 hours at TC.
  • the organic layer was diluted with an aqueous solution of saturated sodium thiosulfate, water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated aqueous solution of sodium chloride, dried over anhydrous sulfuric acid, and concentrated under reduced pressure.
  • the extract and the organic layer were combined, washed with a saturated aqueous solution of sodium hydrogen carbonate (3 ml) and a saturated aqueous solution of sodium chloride (3 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • (+) — (1 S, 2 S) 1,2-epoxy-1,2,6,6-trimethylcyclohexanemethyl acetate (25 mg, 0.12 mmo 1, Yield 48%) and (+) — (1R, 2R) — 1,2-epoxy-1,2,6,6-trimethylcyclohexanemethanol (2 Omg, 0.12mmo1, 48% yield) ).
  • (+)-(1 S, 2 S) 1,2-epoxy-1,2,6,6-trimethylcyclohexanemethylacetate (22 mg, 0.1 Ommo 1, (44% yield) and (+) — (1R, 2R) — 1,2-epoxy — 2,6,6-trimethylcyclohexanemethanol (17mg, 0.1 Ommo1, 44% yield) Obtained.
  • 1,2-Epoxy-1,6,6-chlorohexanemethanol 50 mg, 0.29 mmo 1
  • pinyl acetate 4 Omg, 0.465 mmo 1
  • t-butyl methyl ether 3 ml
  • lipase P 5 Omg, manufactured by Tensaru Pharmaceutical Co., Ltd.
  • optically active 1,2-epoxy-1,2,6,6-trimethylcyclohexanethanol can be industrially advantageously produced with high yield and high optical purity.

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Abstract

On décrit un procédé de production de (+)-(1R,2R)-1,2-époxy-2,6,6-triméthylcyclohexane méthanol représenté par la formule (2) qui se caractérise par le fait qu'on traite le (±)-1,2-époxy-2,6,6triméthylcyclohexane méthylacétate représenté par la formule (1) avec une enzyme capable d'hydrolyser des esters ; et un procédé de production de (+)-(1R,2R)-1,2-époxy-2,6,6triméthylcyclohexane méthanol représenté par la formule (2) qui se caractérise en ce qu'on fait réagir le (±)-1,2-époxy-2,6,6-triméthylcyclohexane méthanol représenté par la formule (3) avec un ester d'acide acétique en présence d'une enzyme capable d'acylation asymétrique pour former du (-)-(1R,2R)-1,2-époxy-2,6,6-triméthylcyclohexane méthylacétate représenté par la formule (4), et qu'on solvolyse le (-)-(1R,2R)-1,2-époxy-2,6,6-triméthylcyclohexane méthylacétate ainsi obtenu.
PCT/JP2001/000882 2000-02-15 2001-02-08 Procede de production de 1,2-epoxy-2,6,6-trimethylcyclohexane methanol optiquement actif Ceased WO2001061027A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
JP2000036545A JP2001224396A (ja) 2000-02-15 2000-02-15 光学活性１，２−エポキシ−２，６，６−トリメチルシクロヘキサンメタノールの製造方法
JP2000-36546 2000-02-15
JP2000036546A JP2001226363A (ja) 2000-02-15 2000-02-15 光学活性１，２−エポキシ−２，６，６−トリメチルシクロヘキサンメタノールの製造法
JP2000-36545 2000-02-15

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454483A2 (fr) * 1990-04-27 1991-10-30 Canon Kabushiki Kaisha Dispositif de détection de vecteur de mouvement

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0454483A2 (fr) * 1990-04-27 1991-10-30 Canon Kabushiki Kaisha Dispositif de détection de vecteur de mouvement

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TAKAYUKI ORITANI ET AL.: "Synthesis and plant growth inhibitory activities of (+)-and (-)-(2Z,4E)-5-(1',2'-epoxy-2',6',6'-trimethylcyclohexyl)-3-methy-2,4-pentadienoic acid", PHYTOCHEMISTRY, vol. 22, no. 9, 1983, pages 1909 - 1912, XP002937470 *

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